Tumor Vaccination Success

Vaccination with tumor-specific antigens is one of several attempted therapies seeking to harness the immune system, but—unfortunately—this strategy has been unsuccessful, possibly because of the immunosuppressive properties of the tumor microenvironment. Kraman et al. (p. 827; see the Perspective by Schreiber and Rowley) have identified immunosuppressive cells of mesenchymal origin in mice comprising 2% of the tumor stromal cell population. They were identified by expression of the fibroblast activation protein–α. Deletion of these cells in lung or pancreatic cancers in mice allowed successful therapeutic vaccination against the tumors, which was dependent on the adaptive immune system and the cytokines interferon-γ and tumor necrosis factor–α. These findings reveal that multiple cell types contribute to the immunosuppressive tumor microenvironment and will inform therapeutic cancer vaccine design.

Abstract

The stromal microenvironment of tumors, which is a mixture of hematopoietic and mesenchymal cells, suppresses immune control of tumor growth. A stromal cell type that was first identified in human cancers expresses fibroblast activation protein–α (FAP). We created a transgenic mouse in which FAP-expressing cells can be ablated. Depletion of FAP-expressing cells, which made up only 2% of all tumor cells in established Lewis lung carcinomas, caused rapid hypoxic necrosis of both cancer and stromal cells in immunogenic tumors by a process involving interferon-γ and tumor necrosis factor–α. Depleting FAP-expressing cells in a subcutaneous model of pancreatic ductal adenocarcinoma also permitted immunological control of growth. Therefore, FAP-expressing cells are a nonredundant, immune-suppressive component of the tumor microenvironment.